WO2005116003A2

WO2005116003A2 - Substituted oxazolobenzoisothiazole dioxide derivatives method for production and use thereof

Info

Publication number: WO2005116003A2
Application number: PCT/EP2005/005321
Authority: WO
Inventors: Stefan Petry; Norbert Tennagels; Reinhard Kirsch; Karl-Heinz Baringhaus
Original assignee: Sanofi-Aventis Deutschland Gmbh
Priority date: 2004-05-29
Filing date: 2005-05-14
Publication date: 2005-12-08
Also published as: AR048974A1; NZ551624A; NO20065926L; CN100594214C; US7453000B2; TW200604193A; ZA200608438B; PA8635301A1; RU2377242C2; EP1753761A2; WO2005116003A3; BRPI0510411A; AU2005247565A1; RU2006147245A; MA28600B1; IL179424A0; DE102004026532A1; MXPA06013818A; CN1960989A; JP2008500976A

Abstract

The invention relates to compounds of formula (I), where the groups have the given meanings and the physiologically-acceptable salts thereof. The compounds are suitable as medicaments for lowering blood sugar levels and for prevention and treatment of diabetes.

Description

Substituted oxazole-benzoisothiazole dioxide derivatives, process for their preparation and their use

The invention relates to substituted oxazole-benzoisothiazole dioxide derivatives and their physiologically tolerable salts.

Structure-like benzoisothiazole dioxide derivatives have already been described in the prior art and their use for the treatment of diabetes (WO 02/11722).

The invention was based on the object of providing compounds with which the prevention and treatment of diabetes mellitus is possible. For this purpose, the compounds should have a therapeutically utilizable blood sugar lowering effect. In particular, the compounds should have an improved activity or an improved ADME profile (absorption, distribution, metabolism and excretion) compared to the compounds from WO 02/11722.

The invention therefore relates to compounds of the formula I

in what mean

X O, C-R2;

YO, C-R2, where one of the groups X and Y is always O and the other is C-R1; R1, R2 independently of one another H, aryl, COOH, (CC ₆ ) -alkylene-COOH, -

COO (CrC ₆ ) alkyl, (C ₁ -C ₆ ) alkylene-COO (C ₁ -C ₆ ) alkyl, (CC ₆ ) alkyl, (C ₂ - C ₆ ) alkenyl, (CC ₆ ) -alkylene-aryl, heterocycle, (CC ₆ ) -alkylene-heterocycle, CF ₃ , OCF ₃ , CN, (CH ₂ ) ι _-6 -OH, 0- (dC ₆ ) -alkyl, CO- (dC ₆ ) - Alkyl, -C (0) 0-alkyl, COOH, CON (R9) (R10) where the aryl radicals and the heterocyclic radicals can be substituted one or more times with F, Cl, Br, (CH ₂ ) o- ₂ θH, ( CrC ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, CF ₃ , OCF ₃ , N (R9) (R10), piperidinone, piperazine, piperazinone, N- (CC ₆ - alkylene) piperazine, N- (CrC ₆ alkylene) piperazinone, morpholine, thiomorpholine, N0 ₂ , CN, 0- (CC ₆ ) alkyl, S (0) o _-2 - (-Cι-C ₆ ) -Alkyl, S0 ₂ -

N (R9) (R10), CO- (CC ₆ ) -alkyl, -COOH, (-C-C ₆ ) -alkylene-COOH, COO (d-C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene -COO (-C-C ₆ ) -alkyl _> (C ₃ -C ₁₀ ) -cycloalkyl, phenyl, these piperidinone, piperazine, piperazinone, N- (dC ₆ -alkylene) -piperazine, N- (-C-C ₆ - Alkylene) piperazinone, morpholine, thiomorpholine and phenyl rings can be substituted one or more times with F, Cl, Br,

(CH ₂ ) o- ₂ θH, COOH, CN, N0 ₂ , -0- (Ct-C ₆ ) -alkyl, -NH-0- (CC ₆ ) -alkyl, - (CO) -NH-0- ( CC ₆ ) alkylene-N (R9) (R10), - (COMd-d alkyl, - (CC ₆ ) alkyl, CF ₃ , OCF ₃ , N (R9) (R10);

R3 H, (-CC ₆ ) alkyl, (CC ₆ ) -alkylene-aryl, -C (0) -aryl, (-C-C ₆ ) -alkylene-

Heterocycle, CO- (-C-C ₆ ) alkyl, the aryl and heterocyclic radicals one or more times with F, Cl, Br, (CC _β ) alkyl, COOH, COO (d- C ₆ ) alkyl, CF. ₃ or OCF ₃ may be substituted;

R4, R5 independently of one another H, F, Cl, Br, (CC ₆ ) -alkyl, CF ₃ , OCF ₃ , N0 ₂ ,

N (R9) (R10), CN, 0- (CC ₆ ) alkyl, CO- (dC ₆ ) alkyl, COOH, (dC ₆ ) alkylene-COOH, CON (R9) (R10), (CC ₆ ) -Alkylene-CON (R9) (R10) _f COO (d- C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-COO (Cι-C ₆ ) -alkyl, S (0) o- ₂ - (-C-C _β ) alkyl, S (0) ₂ - N (R9) (R10), CH ₂ OH, CH ₂ OCH ₃ ;

R6, R7 independently of one another H, F, Cl, Br, (-CC ₆ ) alkyl, cyclopropyl,

Tetrafluorocyclopropyl, difluorocyclopropyl; or R6 and R7 together form the group = CH ₂ ;

R 8 H, CH ₃ , CF ₃ , CH ₂ OH;

R 9 H, (CC ₄ ) alkyl;

R 10 H, (CC ₄ ) alkyl; or

R 9 and R10 together with the N atom to which they are attached form a 3-9 membered ring system;

and their physiologically tolerable salts.

Compounds of the formula I in which one or more radicals have the following meaning are preferred:

R1 aryl, (CC ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (Cι-C ₆ ) alkylene aryl, heterocycle,

(dC ₆ ) alkylene heterocycle, CF ₃ , OCF ₃ , CN, (CH ₂ ) ι- ₆ -OH, 0- (dC ₆ ) alkyl, CO- (CC ₆ ) alkyl, C (0) 0 -alkyl, COOH, CON (R9) (R10), the

Aryl radicals and the heterocyclic radicals can be substituted one or more times with F, Cl, Br, (CH ₂ ) o- ₂ θH, (CC ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ - C ₆ ) -Alkynyl, CF ₃ , OCF ₃ , N (R9) (R10), piperidinone, piperazine, piperazinone, N- (-C-C ₆ -alkylene) -piperazine, N- (-C-C ₆ -alkylene) -piperazinone, Morpholine, thiomorpholine, N0 ₂ , CN, 0- (CC ₆ ) -alkyl, S (O) _0-2 - (CrC ₆ ) -alkyl, S0 ₂ -

N (R9) (R10), CO- (CC ₆ ) -alkyl, -COOH, (dC ₆ ) -alkylene-COOH, -COO (CC ₆ ) -alkyl, (C ₀ -C ₆ ) -alkylene -COO ( dC ₆ ) -alkyl, C ₃ -C ₁₀ -cycloalkyl, phenyl, these being piperidinone, piperazine, piperazinone, N- (dC ₆ -alkylene) -piperazine, N- (dC ₆ -alkylene) -piperazinone, morpholine, thiomorpholine and Phenyl rings can be substituted one or more times with F, Cl, Br,

(CH ₂ ) ₀ -2θH, COOH, CN, N0 ₂ , -0- (dC ₆ ) alkyl, -NH-0- (CC ₆ ) alkyl, - (CO) -NH-0- (dC ₆ ) -Alkylene-N (R9) (R10), - (CO) - (dC ₆ ) -alkyl, - (CC ₆ ) - Alkyl, CF ₃ , OCF ₃ , N (R9) (R10);

R2 H, aryl, COOH, (dC ₆ ) alkylene-COOH, -COO (dC ₆ ) alkyl, (dC ₆ ) -

Alkylene-COO (dC ₆ ) alkyl; (CC ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (CC ₆ ) alkylene aryl, heterocycle, (dC ₆ ) alkylene heterocycle, CF ₃ , OCF ₃ , CN, - (CH ₂ ) ι-

₆ -OH, 0- (dC ₆ ) -alkyl, CO- (dC ₆ ) -alkyl, C (0) 0-alkyl, COOH, CON (R9) (R10), the aryl radicals and the heterocyclic radicals one or more times can be substituted with F, Cl, Br, (CH ₂ ) o-2θH, (C Cδ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, CF ₃ , OCF ₃ , N (R9) (R10), piperidinone, piperazine, piperazinone, N- (dC ₆ -alkylene) -piperazine, N- (C

C ₆ alkylene) piperazinone, morpholine, thiomorpholine, NO ₂ , CN, O- (-C-Ce) - alkyl ,, S (O) _0-2 - (C ₁ -C ₆ ) alkyl, SO ₂ -N (R9) (R10), CO- (CC ₆ ) -alkyl, -COOH, (d-Ce ^ alkylene-COOH. -COO ^ Ce) ^^^, (CrC ₆ ) -alkylene-COO (dC ₆ ) - Alkyl, C ₃ -Cιo-cycloalkyl, phenyl;

R3 H, (CC ₆ ) -alkyl, (dC ₆ ) -alkylene-aryl, -C (0) -aryl, (dC ₆ ) -alkylene-

Heterocycle, CO- (CC ₆ ) alkyl;

R4, R5 independently of one another H, F, Cl, Br, (dC ₆ ) alkyl, CF ₃ , OCF ₃ , N0 ₂ , N (R9) (R10), CN, 0- (dC ₆ ) alkyl, CO- (dC ₆ ) alkyl, COOH, (dC ₆ ) -

Alkylene-COOH, -CON (R9) (R10), (dC ₆ ) -alkylene-CON (R9KR10), COO (dC ₆ ) -alkyl, (d-CeJ-alkylene-COO ^ rCeJ-alkyl, S ^ Jo ^ C Ce) alkyl, S (O) ₂ -N (R9) (R10), CH ₂ OH, CH ₂ OCH ₃ ;

R6, R7 independently of one another H, F, Cl, Br, (CC ₆ ) -alkyl, cyclopropyl,

R 9 H, (-CC ₄ ) alkyl; R 10 H, (CC ₄ ) alkyl; or

R 9 and R 0 together with the N atom to which they are attached form a 3-9 membered ring system;

and their physiologically tolerable salts.

Compounds of the formula I in which one or more radicals have the following meaning are particularly preferred:

R1 phenyl, naphthyl, thionaphthyl, pyridyl, where phenyl, naphthyl,

Thionaphthyl and pyridyl can be substituted one or more times with F, Cl, Br, (CH ₂ ) o. ₂ OH, (dC ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, CF ₃ , OCF ₃ , N (R9) (R10), piperidinone, piperazine, piperazinone, N- (CC ₆ -

Alkylene) -piperazine, N- (dC ₆ -alkylene) -piperazinone, morpholine, thiomorpholine, N0 ₂ , CN, 0- (dC ₆ ) -alkyl, S (0) o- ₂ - (CrC ₆ ) -alkyl, S0 ₂ - N (R9) (R10), CO- (CC ₆ ) -alkyl, COOH, (CC ₆ ) -alkylene-COOH, COO (CC ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-COO ( C ₁ -C ₆ ) alkyl, C ₃ -C ₁₀ cycloalkyl, phenyl, these piperidinone, piperazine, piperazinone, N- (-C ₆ alkylene) -

Piperazine, N- (-C ₆ alkylene) piperazinone, morpholine, thiomorpholine and phenyl rings can be substituted one or more times with F, Cl, Br, (CH ₂ ) ₀ - ₂ θH, COOH, CN, N0 ₂ , - 0- (CC ₆ ) -alkyl, -NH-0- (CC ₆ ) -alkyl, - (CO) -NH-0- (dC ₆ ) -alkylene-N (R9) (R10), - (COHCrC ₆ ) -Alkyl, - (dC ₆ ) -alkyl, CF ₃ , OCF ₃ , N (R9) (R10);

R2 H, (CC ₆ ) -alkyl, COOH, (dC ₆ ) -alkylene-COOH, -COO (CC ₆ ) -alkyl, (d-

C ₆ ) alkylene-COO (C ₁ -C ₆ ) alkyl;

R3 H, (CC ₆ ) -alkyl, (CC ₆ ) -alkylene-aryl, -C (0) -aryl, (dC ₆ ) -alkylene-

Heterocycle, CO- (C ₁ -C ₆ ) alkyl; R4, R5 H;

R6, R7 H;

R 8 H;

R 9 H, (d-d) alkyl;

R 10 H, (CC ₄ ) alkyl;

and their physiologically tolerable salts.

Compounds of the formula I in which one or more radicals have the following meaning are very particularly preferred:

R1 phenyl, where phenyl, naphthyl, thionaphthyl and pyridyl can be substituted one or more times with F, Cl, Br, (CH ₂ ) o _-2 OH, (-C-Ce) alkyl, (C ₂ -C ₆ ) alkenyl , (C ₂ -C ₆ ) alkynyl, CF ₃ , OCF ₃ , N (R9) (R10), piperidinone,

Piperazine, piperazinone, N- (-C ₆ alkylene) -piperazine, N- (dC ₆ alkylene) - piperazinone, morpholine, thiomorpholine, N0 ₂ , CN, 0- (dC ₆ ) alkyl, S (O) _0- ₂ - (-C-C ₆ ) -alkyl, SO ₂ -N (R9) (R10) _, CO- (dC ₆ ) -alkyl, COOH, (CC ₆ ) - alkylene-COOH, COO (dC ₆ ) - Alkyl, (dC ₆ ) -alkylene-COO (-C-C ₆ ) -alkyl, C ₃ - Cio-cycloalkyl, phenyl, these being piperidinone, piperazine, piperazinone,

N- (CrC ₆ -alkylene) -piperazine, N- (dC ₆ -alkylene) -piperazinone, morpholine, thiomorpholine and phenyl pendant can be substituted one or more times with F, Cl, Br, (CH ₂ ) _0-2 -OH, COOH, CN, N0 ₂ , -0- (dC ₆ ) -alkyl, - NH-0- (CC ₆ ) -alkyl, - (CO) -NH-0- (dC ₆ ) -alkylene-N (R9) ( R10), - (CO) - (d- C ₆ ) alkyl, - (CC ₆ ) alkyl, CF ₃ , OCF ₃ , N (R9) (R10);

R2 H, (CC ₆ ) alkyl, -C (0) 0- (dC ₆ ) alkyl, - (dC ₆ ) alkylene-C (0) 0- (dC ₆ ) - Alkyl, -COOH, - (CC ₆ ) alkylene-COOH;

Heterocycle, CO- (C _r C ₆ ) alkyl;

R4, R5 H;

R6, R7 H;

R 8 H;

R 9 H;

R 10 H

and their physiologically tolerable salts.

For explanation: The oxazole residue

has the meaning of the radicals of X equal to C-R2; Y is O; the structure

and the meaning of the radicals of X is O; Y is C-R2; the structure

Furthermore, compounds are preferred in which X is C-R2 and Y is O.

The invention relates to compounds of the formula I, in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.

If radicals or substituents can occur more than once in the compounds of the formula I, they can all independently of one another have the meanings given and be the same or different.

Pharmaceutically acceptable salts are particularly suitable for medical applications due to their higher water solubility compared to the starting or basic compounds. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention are inorganic salts Acids, such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycol, isethione, Lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acid. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts), trometamol (2-amino-2-hydroxymethyl-1, 3-propanediol), diethanolamine, lysine or ethylenediamine.

Salts with a non-pharmaceutically acceptable anion, such as trifluoroacetate, are also within the scope of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic, for example in vitro, applications.

The term "physiologically functional derivative" as used herein denotes any physiologically compatible derivative of a compound of formula I according to the invention, e.g. an ester which, when administered to a mammal, e.g. humans, is able (directly or indirectly) to form a compound of formula I or an active metabolite thereof.

The physiologically functional derivatives also include prodrugs of the compounds according to the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound according to the invention. These prodrugs may or may not work themselves.

The compounds according to the invention can also be present in various polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds according to the invention belong to the scope of the invention and are a further aspect of the invention. In the following, all references to "compound (s) according to formula I" refer to compound (s) of formula I as described above, and their salts, solvates and physiologically functional derivatives as described herein.

An alkyl radical is understood to mean a straight-chain or branched hydrocarbon chain with one or more carbons, e.g. Methyl, ethyl, isopropyl, tert-butyl, hexyl.

The alkyl radicals can be substituted one or more times with suitable groups, such as, for example: F, Cl, Br, I, CF ₃ , NO ₂ , N ₃ , CN, COOH, COO (CC ₆ ) alkyl, CONH ₂ , CONH (CC ₆ ) Alkyl, CON [(dC ₆ ) alkyl] _2ι cycloalkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, 0- (CC ₆ ) - alkyl 0-CO- (dC ₆ ) -Alkyl, 0-CO- (CC ₆ ) -aryl, 0-CO- (CC ₆ ) -heterocycle ,; P0 ₃ H ₂ , SO ₃ H, SO ₂ -NH ₂ , S0 ₂ NH (CC ₆ ) -alkyl, S0 ₂ N [(dC ₆ ) -alkyl] ₂ , S- (-C-C ₆ ) -alkyl, S - (CH ₂ ) _n aryl, S- (CH ₂ ) _n heterocycle, SO- (CC ₆ ) alkyl, SO- (CH ₂ ) _n aryl, SO- (CH ₂ ) _n heterocycle, S0 ₂ - (CrC ₆ ) alkyl, S0 ₂ - (CH ₂ ) _n -aryl, S0 ₂ - (CH ₂ ) _n -heterocycle, S0 ₂ - NH (CH ₂ ) _n -aryl, S0 ₂ -NH (CH ₂ ) _n heterocycle, S0 ₂ -N (dC ₆ ) alkyl) (CH ₂ ) _n aryl, S0 ₂ - N (dC ₆ ) alkyl) (CH ₂ ) _n heterocycle, S0 ₂ -N ((CH ₂ ) _n -Aryl) ₂ ,, S0 ₂ -N ((CH ₂ ) _n - (heterocycle) where n = 0 - 6 and the aryl radical or heterocyclic radical can be used up to twice with F, Cl, Br, OH, CF _{3 )} N0 ₂ , CN, OCF ₃ , 0- (dC ₆ ) alkyl, (CC ₆ ) alkyl, NH ₂ may be substituted; C (NH) (NH ₂ ), NH ₂ , NH- (dC ₆ ) alkyl, N ((dC ₆ ) alkyl) 2, NH (dC ₇ ) acyl, NH-CO- (d- C ₆ ) -Alkyl, NH-COO- (Cι-C ₆ ) -alkyl, NH-CO-aryl, NH-CO heterocycle, NH-COO-aryl, NH-COO heterocycle, NH-CO-NH- (CC ₆ ) -Alkyl, NH-CO-NH-aryl, NH-CO-NH- heterocycle, N (CC ₆ ) -alkyl -CO- (dC ₆ ) -alkyl, N (dC ₆ ) -alkyl -COO- (dC ₆ ) -Alkyl, N (dC ₆ ) -alkyl -CO-aryl, N (CC ₆ ) -alkyl -CO-heterocycle, N (CC ₆ ) -alkyl -COO-aryl, N (-C-C ₆ ) -alkyl -COO -heterocycle, N (CC ₆₎ -alkyl -CO-NH- (dC ₆₎ alkyl), N (CC ₆₎ - alkyl -CO-NH-aryl, N (CC ₆₎ -alkyl -CO-NH-heterocycle , N ((CrC ₆ ) -alkyl) -CO-N- (d- C ₆ ) -alkyl) ₂ , N ((C ₁ -C ₆ ) -alkyl) -CO-N ((C ₁ -C ₆ ) -Alkyl) -aryl, N ((d-C6) -alkyl) -CO-N ((CrC6) -alkyl) heterocycle, N ((C ₁ -C ₆ ) -alkyl) -CO-N- (aryl) ₂ , N ((CC ₆ ) alkyl) -CO-N-

(Heterocycle) ₂ , N (aryl) -CO- (C ₁ -C ₆ ) alkyl, N (heterocycle) -CO- (dC ₆ ) alkyl, N (aryl) - COO- (dC ₆ ) alkyl, N (heterocycle) -COO- (dC ₆ ) alkyl, N (aryl) -CO-aryl,

N (heterocycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (dC ₆ ) -alkyl), N (heterocycle) -CO -NH- (dC ₆ ) -alkyl), N (aryl) -CO-NH-aryl, N (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (CC ₆ ) -alkyl) ₂ , N (heterocycle) -CO-N- (-C-C ₆ ) -alkyl) ₂ , N (Aryl) -CO-N ((C ₁ -C ₆ ) alkyl) aryl, N (heterocycle) -CO-N ((dC ₆ ) alkyl) - aryl, N (aryl) -CO-N- ( Aryl) ₂ , N (heterocycle) -CO-N- (aryl) ₂ , aryl, 0- (CH ₂ ) _n -aryl, O- (CH ₂ ) _n heterocycle, where n = 0-6, where the aryl radical or heterocyclic radical can be substituted one to three times with F, Cl, Br, I, OH, CF ₃ , N0 ₂ , CN, OCF3, 0- (dC ₆ ) -alkyl, (CC ₆ ) -alkyl, NH ₂ , NH (-CC ₆ ) alkyl, N ((dC ₆ ) alkyl) ₂ , S0 ₂ -CH ₃ , COOH, COO- (dC ₆ ) alkyl, CONH ₂ .

An alkenyl radical is understood to mean a straight-chain or branched hydrocarbon chain with two or more carbons and one or more double bonds, such as, for example, vinyl, allyl or pentenyl. The alkenyl radicals can be substituted one or more times with suitable groups, such as: F, Cl, Br, I, CF ₃ , N0 ₂ , N ₃ , CN, COOH, COO (CC ₆ ) alkyl, CONH ₂ , CONH (d- C ₆ ) alkyl, CON [(CrC ₆ ) alkyl] _2, cycloalkyl, (dC ₁₀ ) alkyl, (C ₂ -C ₆ ) alkynyl, 0- (dC ₆ ) alkyl 0-CO- (CC ₆ ) -Alkyl, 0-CO- (C ₁ -C ₆ ) aryl, 0-CO- (dC ₆ ) heterocycle ,;

P0 ₃ H ₂ , SO ₃ H, S0 ₂ -NH ₂ , S0 ₂ NH (dC ₆ ) -alkyl, S0 ₂ N [(CC ₆ ) -alkyl] ₂ , S- (dC ₆ ) -alkyl, S- ( CH ₂ ) _n aryl, S- (CH ₂ ) _n heterocycle, SO- (dC ₆ ) alkyl, SO- (CH ₂ ) _n aryl, SO- (CH ₂ ) _n heterocycle, S0 ₂ - ( CrC ₆ ) alkyl, S0 ₂ - (CH ₂ ) _n -aryl, S0 ₂ - (CH ₂ ) _n -heterocycle, S0 ₂ - NH (CH ₂ ) _n -aryl, S0 ₂ -NH (CH ₂ ) _n - Heterocycle, Sθ ₂ -N (CrC ₆ ) alkyl) (CH ₂ ) n-aryl, S0 ₂ - N (C ₁ -C ₆ ) alkyl) (CH ₂ ) _n heterocycle, Sθ2-N ((CH ₂ ) n-Aryl) ₂ ,, S0 ₂ -N ((CH ₂ ) _n - (heterocycle) ₂ where n can be 0 - 6 and the aryl radical or heterocyclic radical up to twice with F, Cl, Br, OH, CF ₃ , N0 ₂ , CN, OCF ₃ , 0- (dC ₆ ) -alkyl, (CC ₆ ) -alkyl, NH2 may be substituted; C (NH) (NH ₂ ), NH ₂ , NH- (dC ₆ ) - Alkyl, N ((dC ₆ ) alkyl) ₂ , NH (dC ₇ ) acyl, NH-CO- (d-C ₆ ) alkyl, NH-COO- (CC ₆ ) alkyl, NH-CO-aryl , NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH- (CC ₆ ) -alkyl, NH-CO-NH-aryl, NH-CO-NH-heterocycle, N ( C ₁ -C ₆ ) alkyl -CO- (C ₁ -C ₆ ) alkyl, N (dC ₆ ) alkyl -CO O- (C _r C ₆ ) -alkyl, N (dC ₆ ) -alkyl -CO-aryl, N (CC ₆ ) -alkyl -CO-heterocycle, N (CC ₆ ) -alkyl -COO-aryl, N (C ₁ -C ₆ ) -alkyl -COO-heterocycle, N (CC ₆ ) -alkyl -CO-NH- (dC ₆ ) -alkyl), N (dC ₆ ) -alkyl -CO-NH-aryl, N (dC ₆ ) -Alkyl -CO-NH heterocycle, N ((CC ₆ ) -alkyl) -CO-N- (d- C ₆ ) -alkyl) ₂ , N ((dC ₆ ) -alkyl) -CO-N (( Cι-C ₆₎ -alkyl) -aryl, N ((C ₁ -C ₆₎ -alkyl) -CO-N ((C ₁ -C ₆₎ - alkyl) -heterocycle, N ((dC ₆₎ alkyl) -CO-N- (aryl) ₂ , N ((C ₁ -C ₆ ) alkyl) -CO-N- (Heterocycle) ₂ , N (aryl) -CO- (dC ₆ ) alkyl, N (heterocycle) -CO- (dC ₆ ) alkyl, N (aryl) - COO- (CC ₆ ) alkyl, N (heterocycle ) -COO- (CC ₆ ) -alkyl, N (aryl) -CO-aryl,

N (heterocycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO- NH- (-C-C ₆ ) -alkyl), N (heterocycle) -CO-NH- (-C-C ₆ ) -alkyl), N (aryl) -CO-NH-aryl, N (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (dC ₆ ) -Alkyl) ₂ , N (heterocycle) -CO-N- (dC ₆ ) -alkyl) ₂ , N (aryl) -CO-N ((CC ₆ ) -alkyl) -aryl, N (heterocycle) -CO-N ((CC ₆ ) alkyl) aryl, N (aryl) -CO-N- (aryl) ₂ , N (heterocycle) -CO-N- (aryl) ₂ , aryl, 0- (CH ₂ ) _n -aryl , 0- (CH ₂ ) _n heterocycle, where n can be 0-6, where the aryl radical or heterocyclic radical can be substituted one to three times with F, Cl, Br, I, OH, CF ₃ , NO ₂ , CN, OCF ₃ , 0- (dC ₆ ) alkyl, (dC ₆ ) alkyl, NH ₂ , NH (dC ₆ ) alkyl, N ((dC ₆ ) alkyl) ₂ , S0 ₂ -CH ₃₎ COOH, COO- (dC ₆ ) alkyl, CONH ₂ .

An alkynyl radical is understood to mean a straight-chain or branched hydrocarbon chain with two or more carbons and one or more triple bonds, such as e.g. Ethynyl, propynyl, hexynyl.

The alkynyl radicals can be substituted one or more times with suitable groups, such as: F, Cl, Br, I, CF ₃ , N0 ₂ , N ₃ , CN, COOH, COO (dC ₆ ) alkyl, CONH ₂ , CONH (d- C ₆ ) alkyl, CON [(CC ₆ ) alkyl] ₂ , cycloalkyl, (C ₂ -C ₆ ) alkenyl, (dC ₁₀ ) alkyl, 0- (dC ₆ ) - alkyl 0-CO- (CrC ₆ ) -Alkyl, 0-CO- (dC ₆ ) aryl, 0-CO- (dC ₆ ) heterocycle;

P0 ₃ H ₂ , SO ₃ H, S0 ₂ -NH ₂ , S0 ₂ NH (dC ₆ ) -alkyl, S0 ₂ N [(CC ₆ ) -alkyl] ₂ , S- (dC ₆ ) -alkyl, S- ( CH ₂ ) _n aryl, S- (CH ₂ ) _n heterocycle, SO- (dC ₆ ) alkyl, SO- (CH ₂ ) _n aryl, SO- (CH ₂ ) _n heterocycle, Sθ ₂ - ( CC ₆ ) alkyl, S0 ₂ - (CH ₂ ) _n -aryl, S0 ₂ - (CH ₂ ) _n -heterocycle, S0 ₂ - NH (CH ₂ ) _n -aryl, S0 ₂ -NH (CH ₂ ) _n - Heterocycle, S0 ₂ -N (dC ₆ ) alkyl) (CH ₂ ) n-aryl, S0 ₂ - N (dC ₆ ) alkyl) (CH ₂ ) n heterocycle, S0 ₂ -N ((CH ₂ ) _n -Aryl) ₂ ,, S0 ₂ -N ((CH ₂ ) _n - (heterocycle) ₂ where n = 0 - 6 and the aryl radical or heterocyclic radical can be used up to twice with F, Cl, Br, OH, CF ₃ , N0 ₂ , CN, OCF ₃ , 0- (CC ₆ ) alkyl, (dC ₆ ) alkyl, NH ₂ may be substituted; C (NH) (NH ₂ ), NH ₂ , NH- (dC ₆ ) alkyl , N ((dC ₆ ) -alkyl) ₂ , NH (-C-C ₇ ) -acyl, NH-CO- (d-C ₆ ) -alkyl, NH-COO- (C ₁ -C ₆ ) -alkyl, NH -CO-aryl, NH-CO-heterocycle, NH-COO-aryl, NH-COO-heterocycle, NH-CO-NH- (dC ₆ ) -alkyl, NH-CO-NH-aryl, NH-CO-NH- Heterocycle, N (dC ₆ ) alkyl -CO- (dC ₆ ) alkyl, N (CC ₆ ) alkyl -COO- (CC ₆ ) alkyl, N (dC ₆ ) -alkyl -CO-aryl, N (CC ₆ ) -alkyl -CO-heterocycle, N (dC ₆ ) -alkyl -COO-aryl, N (CC ₆ ) -alkyl -COO-heterocycle, N ( CC ₆₎ -alkyl -CO-NH- (dC ₆₎ alkyl), N (CC ₆₎ - alkyl -CO-NH-aryl, N (CC ₆₎ -alkyl -CO-NH-heterocycle, N ((dC ₆ ) -alkyl) -CO-N- (d- C ₆ ) -alkyl) ₂ , N ((dC ₆ ) -alkyl) -CO-N ((CrC ₆ ) -alkyl) -aryl, N ((C ₁ -C ₆ ) alkyl) -CO-N ((C ₁ -C ₆ ) alkyl) heterocycle, N ((CC ₆ ) alkyl) -CO-N- (aryl) ₂ , N ((CC ₆ ) -alkyl) -CO-N-

(Heterocycle) ₂ , N (aryl) -CO- (CC ₆ ) alkyl, N (heterocycle) -CO- (dC ₆ ) alkyl, N (aryl) -COO- (dC ₆ ) alkyl, N (heterocycle ) -COO- (CC ₆ ) -alkyl, N (aryl) -CO-aryl,

N (heterocycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (dC ₆ ) -alkyl), N (heterocycle) -CO -NH- (C ₁ -C ₆ ) alkyl), N (aryl) -CO-NH-aryl, N (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (CC ₆ ) - Alkyl) ₂ , N (heterocycle) -CO-N- (-C-C ₆ ) -alkyl) ₂ , N (aryl) -CO-N ((dC ₆ ) -alkyl) -aryl, N (heterocycle) -CO- N ((dC ₆ ) alkyl) - aryl, N (aryl) -CO-N- (aryl) ₂ , N (heterocycle) -CO-N- (aryl) ₂ , aryl, 0- (CH ₂ ) _n - Aryl, O- (CH ₂ ) _n heterocycle, where n can be 0-6, where the aryl or heterocyclic radical can be substituted one to three times with F, Cl, Br, I, OH, CF ₃ , N0 ₂ , CN, OCF ₃ , 0- (dC ₆ ) alkyl, (CC ₆ ) alkyl, NH ₂ , NH (dC ₆ ) alkyl, N ((-C-C ₆ ) alkyl) ₂ , S0 ₂ - CH ₃ , COOH, COO- (CC ₆ ) alkyl, CONH ₂ .

An aryl radical is understood to mean a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralone, indanyl or indan-1-one-yl radical. The aryl radicals can be substituted one or more times with suitable groups, such as: F, Cl, Br, I, CF ₃ , N0 ₂ , N ₃ , CN, COOH, COO (dC ₆ ) alkyl, CONH ₂ , CONH (d- C ₆ ) alkyl, CON [(dC ₆ ) alkyl] ₂ , cycloalkyl, (dC ₁₀ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, 0- (CC ₆ ) -Alkyl 0-CO- (dC ₆ ) -alkyl, 0-CO- (CC ₆ ) -aryl, 0-CO- (CC ₆ ) -heterocycle ,;

P0 ₃ H ₂ , S0 ₃ H, S0 ₂ -NH ₂ , S0 ₂ NH (dC ₆ ) -alkyl, S0 ₂ N [(dC ₆ ) -alkyl] ₂ , S- (dC ₆ ) -alkyl, S- ( CH ₂ ) _n aryl, S- (CH ₂ ) _n heterocycle, SO- (C _r C ₆ ) alkyl, SO- (CH ₂ ) _n aryl, SO- (CH ₂ ) _n heterocycle, S0 ₂ - (C ₁ -C ₆ ) alkyl, S0 ₂ - (CH ₂ ) _n -aryl, S0 ₂ - (CH ₂ ) _n -heterocycle, S0 ₂ - NH (CH ₂ ) _n -aryl, S0 ₂ -NH ( CH ₂ ) _n heterocycle, S0 ₂ -N (CrC ₆ ) alkyl) (CH ₂ ) _n aryl, S0 ₂ - N (dC ₆ ) alkyl) (CH ₂ ) _n heterocycle, S0 ₂ -N ( (CH ₂ ) _n -aryl) ₂ ,, S0 ₂ -N ((CH ₂ ) _n - (heterocycle) ₂ where n = 0 - 6 and the aryl radical or heterocyclic radical can be substituted up to twice with F, Cl, Br, OH, CF ₃ , NO ₂ , CN, OCF ₃ , 0- (dC ₆ ) -alkyl, (dC ₆ ) -alkyl, NH ₂ ;

C (NH) (NH ₂ ), NH ₂ , NH- (-C-C ₆ ) alkyl, N ((CC ₆ ) alkyl) ₂ , NH (CC ₇ ) acyl, NH-CO- (d- C ₆ ) -alkyl, NH-COO- (CC ₆ ) -alkyl, NH-CO-aryl, NH-CO heterocycle, NH-COO-aryl, NH-COO heterocycle, NH-CO-NH- (dC ₆ ) -Alkyl, NH-CO-NH-aryl, NH-CO-NH- heterocycle, N (dC ₆ ) -alkyl -CO- (CC ₆ ) -alkyl, N (CC ₆ ) -alkyl -COO- (CC ₆ ) -Alkyl, N (CC ₆ ) -alkyl -CO-aryl, N (CC ₆ ) -alkyl -CO-heterocycle, N (dC ₆ ) -alkyl -COO-aryl, N (CC ₆ ) -alkyl -COO-heterocycle , N (CC ₆₎ -alkyl -CO-NH- (CC ₆₎ alkyl), N (dC ₆₎ - alkyl -CO-NH-aryl, N (dC ₆₎ -alkyl -CO-NH-heterocycle, N ((dC ₆ ) -alkyl) -CO-N- (-C-C ₆ ) -alkyl) ₂ , N ((C ₁ -C ₆ ) -alkyl) -CO-N ((CC ₆ ) -alkyl) -aryl , N ((C ₁ -C ₆ ) alkyl) -CO-N ((C ₁ -C ₆ ) alkyl) heterocycle, N ((dC ₆ ) alkyl) -CO-N- (aryl) ₂ , N ((CC ₆ ) alkyl) -CO-N-

(Heterocycle) ₂ , N (aryl) -CO- (CC ₆ ) -alkyl, N (heterocycle) -CO- (CC ₆ ) -alkyl, N (aryl) -COO- (C _r C ₆ ) -alkyl, N (Heterocycle) -COO- (dC ₆ ) alkyl, N (aryl) -CO-aryl,

N (heterocycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (dC ₆ ) -alkyl), N (heterocycle) -CO -NH- (CC ₆ ) alkyl), N (aryl) -CO-NH-aryl, N (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (dC ₆ ) alkyl) ₂ , N (heterocycle) -CO-N- (-CC ₆ ) -alkyl) ₂ , N (aryl) -CO-N ((-CC ₆ ) alkyl) aryl, N (heterocycle) -CO-N ((CC ₆ ) alkyl) aryl, N (aryl) -CO-N- (aryl) ₂ , N (heterocycle) -CO-N- (aryl) ₂ , aryl, 0- (CH ₂ ) _n -aryl , O- (CH ₂ ) _n heterocycle, where n can be 0-6, where the aryl or heterocyclic radical can be substituted one to three times with F, Cl, Br, I, OH, CF ₃ , NO ₂ , CN, OCF ₃ , 0- (dC ₆ ) alkyl, (CC ₆ ) alkyl, NH ₂ , NH (CC ₆ ) alkyl, N ((CC ₆ ) alkyl) ₂ , SO2-CH3, COOH, COO- (dC ₆ ) alkyl, CONH ₂ .

A cycloalkyl radical is understood to mean a ring system containing one or more rings which is saturated or partially unsaturated (with one or two double bonds) and which is composed exclusively of carbon atoms, such as cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl. The cycloalkyl radicals can be substituted one or more times with suitable groups, such as: F, Cl, Br, I, CF ₃ , N0 ₂ , N ₃ , CN, COOH, COO (C ₁ -C ₆ ) alkyl, CONH ₂ , CONH (dC ₆ ) alkyl, CON [(dC ₆ ) alkyl] ₂ , cycloalkyl, (dC ₁₀ ) alkyl, (C ₂ -C ₆ ) - Alkenyl, (C ₂ -C ₆ ) alkynyl, 0- (CC ₆ ) alkyl 0-CO- (CC ₆ ) alkyl, 0-CO- (CrC ₆ ) aryl, O- CO- (CC ₆ ) heterocycle ,;

P0 ₃ H ₂ , S0 ₃ H, S0 ₂ -NH ₂ , S0 ₂ NH (CC ₆ ) -alkyl, S0 ₂ N [(dC ₆ ) -alkyl] ₂ , S- (dC ₆ ) -alkyl, S- ( CH ₂ ) _n aryl, S- (CH ₂ ) _n heterocycle, SO- (CC ₆ ) alkyl, SO- (CH ₂ ) _n aryl, SO- (CH ₂ ) _n heterocycle, S0 ₂ - ( C ₁ -C ₆ ) alkyl, S0 ₂ - (CH ₂ ) _n -aryl, S0 ₂ - (CH ₂ ) _n -heterocycle, S0 ₂ - NH (CH ₂ ) _n -aryl, S0 ₂ -NH (CH ₂ ) _n heterocycle, S0 ₂ -N (CC ₆ ) alkyl) (CH ₂ ) n-aryl, S0 ₂ - N (dC ₆ ) alkyl) (CH ₂ ) n heterocycle, S0 ₂ -N ((CH ₂ ) _n -Aryl) ₂ ,, S0 ₂ -N ((CH ₂ ) _n - (heterocycle) ₂ where n = 0 - 6 and the aryl radical or heterocyclic radical can be up to twice with F, Cl, Br, OH, CF ₃ , N0 ₂ , CN, OCF ₃ , 0- (-C-C ₆ ) alkyl, (dC ₆ ) alkyl, NH ₂ may be substituted;

C (NH) (NH ₂ ), NH ₂ , NH- (CC ₆ ) -alkyl, N ((-C-C ₆ ) -alkyl) ₂ , NH (CC ₇ ) -acyl, NH-CO- (d- C ₆ ) -alkyl, NH-COO- (CC ₆ ) -alkyl, NH-CO-aryl, NH-CO heterocycle, NH-COO-aryl, NH-COO heterocycle, NH-CO-NH- (dC ₆ ) -Alkyl, NH-CO-NH-aryl, NH-CO-NH- heterocycle, N (CC ₆ ) alkyl -CO- (-C-C ₆ ) alkyl, N (dC ₆ ) alkyl -COO- (CC ₆ ) -alkyl, N (CC ₆ ) -alkyl -CO-aryl, N (dC ₆ ) -alkyl -CO-heterocycle, N (dC ₆ ) -alkyl -COO-aryl, N (CC ₆ ) -alkyl -COO Heterocycle, N (dC ₆ ) -alkyl -CO-NH- (C ₁ -C ₆ ) -alkyl), N (CC ₆ ) -alkyl -CO-NH-aryl, N (CC ₆ ) -alkyl -CO- NH heterocycle, N ((C ₁ -C ₆ ) alkyl) -CO-N- (C ₁ - C ₆ ) alkyl) ₂ , N ((-C-C6) alkyl) -CO-N ((dC ₆ ) alkyl) aryl, N ((C ₁ -C ₆ ) alkyl) -CO-N ((C ₁ -C ₆ ) alkyl) heterocycle, N ((dC ₆ ) alkyl) -CO- N- (Aryl) 2, N ((dC ₆ ) -alkyl) -CO-N- (heterocycle) ₂ , N (aryl) -CO- (CC ₆ ) -alkyl, N (heterocycle) -CO- (dC ₆ ) -Alkyl, N (aryl) - COO- (-C-C ₆ ) -alkyl, N (heterocycle) -COO- (CC ₆ ) -alkyl, N (aryl) -CO-aryl,

N (heterocycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (CC ₆ ) -alkyl), N (heterocycle) -CO -NH- (dC ₆ ) -alkyl), N (aryl) -CO-NH-aryl, N (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (dC ₆ ) -alkyl) ₂ , N (heterocycle) -CO-N- (dC ₆ ) -alkyl) ₂ , N (aryl) -CO-N ((CrC ₆ ) -alkyl) -aryl, N (heterocycle) -CO-N ((CC ₆ ) Alkyl) - aryl, N (aryl) -CO-N- (aryl) ₂ , N (heterocycle) -CO-N- (aryl) ₂ , aryl, 0- (CH ₂ ) _n -aryl, O- ( CH ₂ ) _n heterocycle, where n can be 0-6, where the aryl radical or heterocyclic radical can be substituted one to three times with F, Cl, Br, I, OH, CF ₃ , NO ₂ , CN, OCF ₃ , 0- (dC ₆ ) alkyl, (dC ₆ ) alkyl, NH ₂ , NH (CC ₆ ) alkyl, N ((C ₁ -C ₆ ) alkyl) ₂ , S0 ₂ -CH ₃ , COOH , COO- (dC ₆ ) alkyl, CONH ₂ . The term heterocycle or heterocyclic radical means rings and ring systems which, in addition to carbon, also contain heteroatoms, such as nitrogen, oxygen or sulfur. Ring systems also belong to this definition, in which the heterocycle or the heterocyclic radical is condensed with benzene nuclei.

Suitable "heterocyclic rings" or "heterocyclic radicals" are acridinyl, azocinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, carbazidazolinyl, carbazidazolinyl, carbazidazolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1, 5,2-dithiazinyl, dihydrofuro [2,3-b] tetrahydrofuran, furyl, furazanyl, imidazolidinyl, imidazolinyl, 1 imidazolinyl H-lndazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1, 2,3-oxadiazolyl, 1 , 2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1, 3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, Ph enoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, Purynyl, pyranyl, pyrazinyl, Pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, Pyhdooxazole, pyridoimidazoles, Pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, Tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1, 2,5-thiadazinyl, thiazolyl, 1, 2,3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1, 2,5-thiadiazolyl, 1, 3,4-thiadiazolyl, thienyl, Triazolyl, tetrazolyl and xanthenyl.

Pyridyl represents both 2-, 3- and 4-pyridyl. Thienyl represents both 2- and 3- thienyl. Furyl stands for both 2- and 3-furyl.

The corresponding N-oxides of these compounds are also included, e.g. 1-oxy-2-, 3- or 4-pyridyl.

One or more benzo-fused derivatives of these are also included Heterocycles.

The heterocyclic rings or heterocyclic radicals can be substituted one or more times with suitable groups, such as: F, Cl, Br, I, CF ₃ , N0 ₂ , N ₃ , CN, COOH, COO (dC ₆ ) alkyl, CONH ₂ , CONH (CC ₆ ) alkyl, CON [(dC ₆ ) alkyl] ₂ , cycloalkyl, (d-Cιo) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, 0- (dC ₆ ) alkyl 0-CO- (CC ₆ ) alkyl, O-CO- (CC ₆ ) aryl, 0-CO- (CC ₆ ) heterocycle;

P0 ₃ H ₂ , SO ₃ H, S0 ₂ -NH ₂ , S0 ₂ NH (dC ₆ ) -alkyl, S0 ₂ N [(dC ₆ ) -alkyl] ₂ , S- (CC ₆ ) -alkyl, S- ( CH ₂ ) _n aryl, S- (CH ₂ ) _n heterocycle, SO- (dC ₆ ) alkyl, SO- (CH ₂ ) _n aryl, SO- (CH ₂ ) _n heterocycle, S0 ₂ - ( dC ₆ ) -alkyl, S0 ₂ - (CH ₂ ) _n -aryl, S0 ₂ - (CH ₂ ) _n -heterocycle, S0 ₂ - NH (CH ₂ ) _n -aryl, S0 ₂ -NH (CH ₂ ) _π - Heterocycle, S0 ₂ -N (dC ₆ ) -alkyl) (CH ₂ ) _n -aryl, S0 ₂ - N (-C-C ₆ ) -alkyl) (CH ₂ ) _n -heterocycle, S0 ₂ -N ((CH ₂ ) n-Aryl) 2,, S0 ₂ -N ((CH ₂ ) _n - (heterocycle) ₂ where n can be 0 - 6 and the aryl radical or heterocyclic radical up to twice with F, Cl, Br, OH, CF ₃ , N0 ₂ , CN, OCF ₃ , 0- (dC ₆ ) alkyl, (dC ₆ ) alkyl, NH ₂ may be substituted;

C (NH) (NH ₂ ), NH ₂ , NH- (dC ₆ ) alkyl, N ((CC ₆ ) alkyl) ₂ , NH (dC ₇ ) acyl, NH-CO- (d- C ₆ ) -Alkyl, NH-COO- (dC ₆ ) -alkyl, NH-CO-aryl, NH-CO heterocycle, NH-COO-aryl, NH-COO heterocycle, NH-CO-NH- (CC ₆ ) alkyl , NH-CO-NH aryl, NH-CO-NH heterocycle, N (CC ₆ ) alkyl -CO- (dC ₆ ) alkyl, N (CC ₆ ) alkyl -COO- (dC ₆ ) alkyl , N (dC ₆ ) -alkyl -CO-aryl, N (CC ₆ ) -alkyl -CO-heterocycle, N (CC ₆ ) -alkyl -COO-aryl, ^' N (CC ₆ ) -alkyl -COO-heterocycle, N (dC ₆ ) alkyl -CO-NH- (C ₁ -C ₆ ) alkyl), N (CC ₆ ) alkyl -CO-NH-aryl, N (CC ₆ ) alkyl -CO-NH heterocycle , N ((CC ₆ ) -alkyl) -CO-N- (-Cι- C ₆ ) -alkyl) ₂ , N ((dC ₆ ) -alkyl) -CO-N ((Cι-C ₆ ) -alkyl) - Aryl, N ((dC ₆ ) -alkyl) -CO-N ((-Cι-C ₆ ) - alkyl) heterocycle, N ((dC ₆ ) -alkyl) -CO-N- (aryl) ₂ , N (( CC ₆ ) -alkyl) -CO-N- (heterocycle) ₂ , N (aryl) -CO- (C ₁ -C ₆ ) -alkyl, N (heterocycle) -CO- (dC ₆ ) -alkyl, N (aryl ) - COO- (CC ₆ ) -alkyl, N (heterocycle) -COO- (dC ₆ ) -alkyl, N (aryl) -CO-aryl,

N (heterocycle) -CO-aryl, N (aryl) -COO-aryl, N (heterocycle) -COO-aryl, N (aryl) -CO-NH- (dC ₆ ) -alkyl), N (heterocycle) -CO -NH- (dC ₆ ) -alkyl), N (aryl) -CO-NH-aryl, N (heterocycle) -CO-NH-aryl, N (aryl) -CO-N- (dC ₅ ) -alkyl) ₂ , N (heterocycle) -CO-N- (dC ₆ ) -alkyl) ₂ , N (aryl) -CO-N ((C ₁ -C ₆ ) -alkyl) -aryl, N (heterocycle) -CO-N ( (dC ₆ ) alkyl) aryl, N (aryl) -CO-N- (aryl) ₂ , N (heterocycle) -CO-N- (aryl) ₂ , aryl, 0- (CH ₂ ) _n -aryl, O- (CH ₂ ) _n heterocycle, where n = 0-6, where the aryl radical or Heterocyclic radical can be substituted one to three times with F, Cl, Br, I, OH, CF ₃ , N0 ₂ , CN, OCF ₃ , 0- (-C-C ₆ ) alkyl, (CC ₆ ) alkyl, NH ₂ , NH (CC ₆ ) alkyl, N ((CC ₆ ) alkyl) ₂ , S0 ₂ -CH ₃₎ COOH, COO- (dC ₆ ) alkyl, CONH ₂ .

The amount of a compound of formula I required to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. In general, the daily dose is in the range from 0.3 mg to 100 mg (typically from 3 mg and 50 mg) per kilogram of body weight per day, for example 3-10 mg / kg / day. An intravenous dose can be, for example, in the range from 0.3 mg to 1.0 mg / kg, which can suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes can contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single doses can contain, for example, from 1 mg to 10 g of the active ingredient. Thus, ampoules for injections can contain, for example, from 1 mg to 100 mg, and orally administrable single-dose formulations, such as tablets or capsules, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. For the therapy of the abovementioned conditions, the compounds of the formula I themselves can be used as a compound, but they are preferably in the form of a pharmaceutical composition with a compatible carrier. The carrier must of course be compatible, in the sense that it is compatible with the other components of the composition and is not harmful to the health of the patient. The carrier can be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which can contain from 0.05% to 95% by weight of the active ingredient. Further pharmaceutically active substances can also be present, including further compounds of the formula I. The pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which essentially consist in the constituents comprising pharmacologically acceptable carriers and / or auxiliaries be mixed.

Pharmaceutical compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration in each individual case depends on the type and severity of the to be treated State and on the type of compound used according to formula I is dependent. Coated formulations and coated slow-release formulations also fall within the scope of the invention. Formulations which are resistant to acid and gastric juice are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration can be present in separate units, such as capsules, capsules, lozenges or tablets, each of which contains a certain amount of the compound of the formula I; as powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions can be prepared by any suitable pharmaceutical method comprising a step in which the active ingredient and the carrier (which can consist of one or more additional ingredients) are brought into contact. In general, the compositions are prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is shaped if necessary. For example, a tablet can be produced by compressing or molding a powder or granulate of the compound, optionally with one or more additional components. Pressed tablets can be prepared by tabletting the compound in free-flowing form, such as a powder or granulate, optionally mixed with a binder, lubricant, inert diluent and / or a (several) surface-active / dispersing agent in one suitable machine. Molded tablets can be made by molding the powdered compound moistened with an inert liquid diluent in a suitable machine.

Pharmaceutical compositions suitable for oral (sublingual) administration include lozenges containing a compound of Formula I with a flavor, usually sucrose and acacia or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerin or sucrose and gum arabic.

Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula I, which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although they can also be administered subcutaneously, intramuscularly or intradermally as an injection. These preparations can preferably be prepared by mixing the compound with water and making the solution obtained sterile and isotonic with the blood. Injectable compositions according to the invention generally contain from 0.1 to 5% by weight of the active compound.

Suitable pharmaceutical compositions for rectal administration are preferably in the form of single-dose suppositories. These can be prepared by mixing a compound of the formula I with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.

Suitable pharmaceutical compositions for topical use on the skin are preferably in the form of an ointment, cream, lotion, paste, spray, aerosol or oil. Vaseline, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances can be used as carriers. The active ingredient is generally present in a concentration of 0.1 to 15% by weight of the composition, for example 0.5 to 2%. Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal applications can be presented as individual patches which are suitable for long-term close contact with the patient's epidermis. Such plasters suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is approximately 1% to 35%, preferably approximately 3% to 15%. As a special possibility, the active ingredient can be released by electrotransport or iontophoresis, as described for example in Pharmaceutical Research, 2 (6): 318 (1986).

The compound (s) of the formula (I) can also be used in combination with other

Active substances are administered.

The following are also suitable as active ingredients for the combination preparations: all antidiabetic agents mentioned in the Red List 2003, Chapter 12. They can be combined with the compounds of the formula I according to the invention in particular to improve the synergistic effect. The active ingredient combination can be administered either by separate administration of the active ingredients to the patient or in the form of combination preparations in which several active ingredients are present in a pharmaceutical preparation. Most of the active ingredients listed below are disclosed in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001.

Antidiabetics include insulin and insulin derivatives, such as Lantus ^® (see www.lantus.com) or HMR 1964 fast-acting insulins (see US 6,221, 633), GLP-1 derivatives such as those described in WO 97/26265, WO 99/03861, WO

01/04156, WO 00/34331, WO00 / 34332, W091 / 11457 and US 6,380,357, and orally active hypoglycemic active substances.

The oral. active hypoglycemic agents preferably include

Sulphonyl ureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, Potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 by Novo Nordisk A / S, insulin sensitizers, inhibitors of liver enzymes involved in stimulating gluconeogenesis and / or glycogenolysis, modulators of glucose uptake , lipid-modifying compounds such as antihyperlipidemic agents and antilipidemic agents, compounds that reduce food intake, PPAR and PXR agonists and agents that act on the ATP-dependent potassium channel of the beta cells.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor, such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin.

In one embodiment of the invention, the compounds of the formula I are used in combination with a cholesterol absorption inhibitor, such as e.g. Ezetimibe, Tiqueside, Pamaqueside.

In one embodiment of the invention, the compounds of the formula I are used in combination with a PPAR gamma agonist, e.g. Rosiglitazone, pioglitazone, JTT-501, Gl 262570.

In one embodiment of the invention, the compounds of the formula I in combination with PPAR alpha agonist, e.g. GW 9578, GW 7647.

In one embodiment of the invention, the compounds of the formula I are used in combination with a mixed PPAR alpha / gamma agonist, e.g. GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in PCT / US 11833, PCT / US 11490, DE10142734.4.

In one embodiment of the invention, the compounds of the formula I in combination with a fibrate, such as e.g. Fenofibrate, clofibrate, bezafibrate.

In one embodiment of the invention, the compounds of the formula I in Combination with an MTP inhibitor, such as Implitapide, BMS-201038, R-103757, administered.

In one embodiment of the invention, the compounds of the formula I are used in combination with bile acid absorption inhibitor (see, for example, US 6,245,744 or US 6,221, 897), such as e.g. HMR 1741.

In one embodiment of the invention, the compounds of the formula I in combination with a CETP inhibitor, such as e.g. JTT-705.

In one embodiment of the invention, the compounds of the formula I are used in combination with a polymeric bile acid adsorber, such as e.g. Cholestyramine, Colesevelam administered.

In one embodiment of the invention, the compounds of the formula I are used in combination with an LDL receptor (see US 6,342,512), e.g. HMR1171, HMR1586.

In one embodiment of the invention, the compounds of the formula I in combination with an ACAT inhibitor, such as e.g. Avasimibe administered.

In one embodiment of the invention, the compounds of the formula I in combination with an antioxidant, such as e.g. OPC-14117.

In one embodiment of the invention, the compounds of the formula I in combination with a lipoprotein lipase inhibitor, such as e.g. NO-1886.

In one embodiment of the invention, the compounds of the formula I are used in combination with an ATP citrate lyase inhibitor, e.g. SB-204990.

In one embodiment of the invention, the compounds of the formula I in combination with a squalene synthetase inhibitor, such as, for example, BMS-188494, administered.

In one embodiment of the invention, the compounds of the formula I are antagonized in combination with a lipoprotein (a), e.g. CI-1027 or nicotinic acid.

In one embodiment of the invention, the compounds of the formula I in combination with a lipase inhibitor, such as e.g. Orlistat administered.

In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin.

In one embodiment the compounds of formula I are used in combination with a sulphonylurea, e.g. Tolbutamide, glibenclamide, glipizide or glimepiride administered.

In one embodiment, the compounds of formula I in combination with a biguanide, such as e.g. Metformin.

In another embodiment, the compounds of formula I in combination with a meglitinide, such as e.g. Repaglinide.

In one embodiment, the compounds of formula I in combination with a thiazolidinedione, such as e.g. Troglitazone, ciglitazone, pioglitazone, rosiglitazone or those described in WO 97/41097 by Dr. Reddy's Research Foundation disclosed compounds, in particular 5 - [[4 - [(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy] phenyl] methyl] -2,4-thiazolidinedione.

In one embodiment, the compounds of the formula I are administered in combination with a σ-glucosidase inhibitor, such as, for example, miglitol or acarbose. In one embodiment, the compounds of the formula I are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide.

In one embodiment, the compounds of formula I are used in combination with more than one of the aforementioned compounds, e.g. in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.

In a further embodiment, the compounds of the formula I are used in combination with CART modulators (see "Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M.:Hormone and Metabolie Research (2001), 33 (9), 554-558), NPY antagonists e.g. Naphthalene-1-sulfonic acid {4 - [(4-amino-quinazolin-2-ylamino) methylj-cyclohexylmethyl} amide; hydrochloride (CGP 71683A)), MC4 agonists (e.g. 1-amino-1, 2,3,4-tetrahydro-naphthalene-2-carboxylic acid [2- (3a-benzyl-2-methyl-3-oxo

2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (4-chlorophenyl) -2-oxo-ethylj-amide; (WO 01/91752)), orexin antagonists (e.g. 1- (2-methyl-benzoxazol-6-yl) -3- [1, 5] naphthyridin-4-yl-urea; hydrochloride (SB-334867-A) ), H3 agonists (3-cyclohexyl-1- (4,4-dimethyl-1, 4,6,7-tetrahydro-imidazo [4,5-c] pyridin-5-yl) propan-1-one oxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g. [2-methyl-9- (2,4,6-trimethylphenyl) -9H-1,3,9-triaza-fluoren-4-yl] dipropyl amine (WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists, /? 3 agonists (e.g. 1- (4-chloro-3-methanesulfonylmethyl-phenyl) -2- [2- (2,3- dimethyl-1 H-indol-6-yloxy) ethylaminoj-ethanol; hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone) agonists, CCK-A agonists (e.g. {2- [4- (4- Chloro-2,5-dimethoxy-phenyl) -5- (2-cyclohexyl-ethyl) -thiazol-2-ylcarbamoyl] -5,7-dimethyl-indol-1 -yl} -acetic acid trifluoroacetic acid salt (WO 99/15525) ); Serotonin reuptake inhibitors (e.g. dexfenfluramines), mixed sertonin and noradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g. 1- (3-ethyl-benzofuran-7-yl) piperazine oxalic acid salt (WO 01/09111) , Bombesin agonists, galanin antagonists, growth hormone (e.g. human growth hormone), growth hormone releasing compounds (6-benzyloxy-1- (2-diisopropylamino-ethylcarbamoyl) -3,4-dihydro-1 H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)), TRH Agonists (see e.g. EP 0 462 884) decoupling protein 2 or 3 modulators, leptin agonists (see e.g. Lee, Daniel W .; Leinung, Matthew C; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26 (9), 873-881),

DA agonists (bromocriptine, doprexin), lipase / amylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO 00/78312), RXR modulators or TR - # agonists.

In one embodiment of the invention, the further active ingredient is leptin; see e.g. "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2 (10), 1615-1622.

In one embodiment, the further active ingredient is dexamphatamine or amphetamine.

In one embodiment, the further active ingredient is a blood pressure lowering agent, e.g. an ACE inhibitor.

In one embodiment, the further active ingredient is fenfluramine or dexfenfluramine.

In another embodiment, the further active ingredient is sibutramine.

In one embodiment, the further active ingredient is orlistat.

In one embodiment, the further active ingredient is mazindol or phentermine.

In one embodiment, the compounds of formula I in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob / Caromax ^® (Zunft HJ; et al, Carob pulp preparation for treatment of hypercholesterolemia. ADVANCES IN THERAPY (2001 Sep-Oct), 18 (5), 230-6.) Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt / Main)). The combination with Caromax ^® can be done in one preparation or by separate administration of compounds of formula I and Caromax ^® . Caromax ^® can also be administered in the form of food, such as in baked goods or granola bars.

It goes without saying that any suitable combination of the compounds according to the invention with one or more of the abovementioned compounds and optionally one or more further pharmacologically active substances is considered to be within the scope of the present invention.

JTT-501 The following examples serve to illustrate the invention, but without restricting it.

The effectiveness of the compounds was tested as follows:

Enzymatic test systems for the detection of the inhibition of a phosphatase

The compounds of formula I were tested in an in vitro assay for their phosphatase inhibitory activity. The enzyme preparation and the execution of the assay were carried out as follows.

Obtaining the enzyme preparation: A) Cell culture:

Sf9 cells (= cell type from Spodoptera frugiperda; available from invitrogen) are stored in spinner flasks at 28 ° C in Grace's supplemented medium (Gibco-BRL) with 10% heat-inactivated fetal calf serum (Gibco-BRL) according to the protocol of Summers and Smith ( A Manual for Methods for Baculoviruns Vectors and Insect Culture Procedures [Bulletin No. 15555]. Texas A & M

University, Texas Agricultural Experiment Station, College Station, TX, 1987).

Construction of recombinant baculovirus transfer vectors: encoding cDNA _. for the regulatory and catalytic domains of human PTP1 B, but without the carboxy-terminal hydrophobic region (corresponding to 1-299 aa) was obtained via polymerase chain reaction via primers with attached cloning sites and suitable cDNA matrices (available, for example, from invitrogen) and then in baculovirus expression vectors ( Amersham Pharmacia Biotech.). The recombinant baculoviruses were produced using the Bac-to-Bac baculovirus expression system (available from Gibco-BRL). The gene was cloned into the pFASTBAC donor plasmid (available from Life Technologies). The resulting plasmid was transformed into competent DH10BAC Escherichia coli cells (available from Life Technologies). After transposition and antibiotic selection, the recombinant plasmid DNA was isolated from selected E. coli colonies and then used for the transfection of Sf9 insect cells. The virus particle in the The supernatant medium was amplified three times to a viral stock volume of 500 ml.

B) Production of recombinant protein:

Baculovirus infection of a 500 ml spinner culture of Sf9 cells was carried out essentially as described by Summers and Smith (see above). Sf9 cells at a density of 1-3 x 10 ⁶ cells / ml were centrifuged

300 g pelleted for 5 min, the supernatant was removed and the cells were resuspended at a density of 1 × 10 ⁷ cells / ml in a suitable recombinant viral stock (MOI 10). After shaking gently for 1.5 hours at room temperature, fresh medium was added to achieve a cell density of 1 × 10 ⁶ cells / ml. The cells were then cultured in suspension at 28 ° C for appropriate periods after post-infection.

C) Cellular fractionation and total cell extracts from infected Sf9 cells:

After post-infection, aliquots were subjected to protein expression analysis by SDS-PAGE and Western blot analysis. The cellular

Fractionation was carried out as described (Cromlish, W. and Kennedy, B. Biochem. Pharmacol. 52: 1777-1785, 1996). Whole cell extracts were obtained from 1 ml aliquots of the infected Sf9 cells after certain times of post-infection. The pelleted cells (300xg, 5 min) were washed once in phosphate-buffered saline (4 ° C.), resuspended in 50 μl water and disrupted by repeated freezing / thawing. Protein concentrations were determined using the Bradford method and bovine serum albumin as the standard.

Carrying out the assay:

A) Dephosphorylation of a phosphopeptide:

This assay is based on the release of phosphate from a consensus substrate peptide, which is in the nanomolar concentration range by the malachite green ammonium molybdate method (Lanzetta, PA, Alvarez, LJ, Reinach, PS, Candia, OA Anal Biochem. 100: 95-97, 1979) adapted for the microtiter plate format is detected. The dodecatris phosphopeptide, TRDIYETDYYRK (Biotrend, Cologne) corresponds to amino acids 1142-1153 of catalytic domain of the insulin receptor and is (auto) phosphorylated on the tyrosine residues 1146, 1150, and 1151. The recombinant hPTPI B was diluted with assay buffer (40 mM Tris / HCl, pH 7.4, 1 mM EDTA, 20 mM DTT), corresponding to one activity of 1000-1500 nmol / min / mg protein and (a 20 μl portion) then pre-incubated (15 min, 30 ° C) in the absence or presence of the

Test substance (5 μl) in the desired concentration (final conc. DMSO 2% max.) In a total volume of 90 μl (assay buffer). At the start of the dephosphorylation reaction, the peptide substrate (10 μl, preheated to 30 ° C.) for the pre-incubated enzyme preparation with or without test substance (final concentration 0.2-200 μM) was added and the incubation continued for 1 hour.

The reaction was stopped by adding 100 ul malachite green hydrochloride (0.45%, 3 parts), ammonium molybdate tetrahydrate (4.2% in 4N HCl, 1 part) and 0.5% Tween 20 as a stop solution. After 30 min incubation at 22 ° C for the development of the color, the absorption at 650 nm was determined with the aid of a microtiter plate reader (Molecular Devices).

Samples and blank values were measured as triple values. The PTP1 B activity was calculated as nanomoles of released phosphate per min and mg protein with potassium phosphate as standard. The inhibition of the recombinant hPTPI B by test substances was calculated as a percentage of the phosphatase control. The IC ₅ significant show o values

Agreement with a four-parameter nonlinear logistic regression curve. p-Nitrophenylphosphate: This assay is based on the absorption change of the non-physiological

Substrate p-nitrophenyl phosphate during the cleavage to nitrophenol under standard conditions (Tonks, NK, Diltz, CD :, Fischer, EHJ Biol. Chem. 263: 6731-6737, 1988; Burke TR, Ye, B., Yan, XJ, Wang, SM, Jia, ZC, Chen, L, Zhang, ZY, Barford, D. Biochemistry 35: 15989-15996, 1996). The inhibitors are pipetted in a suitable dilution to the reaction mixtures which contain 0.5-5 mM p-nitrophenyl phosphate. The following buffers were used (total volume 100 μl): (a) 100 mM sodium acetate (pH 5.5), 50mM NaCl, 0.1% (w / v) bovine serum albumin, 5mM glutathione, 5mM DTT, 0.4mM EGTA and 1mM EDTA; (b) 50mM Hepes / KOH (pH 7.4), 100mM NaCl, 0.1% (w / v) bovine serum albumin, 5mM glutathione, 5mM DTT and 1mM EDTA. The reaction was started by adding enzyme and carried out in microtiter plates at 25 ° C. for 1 hour. The reaction was terminated by adding 100 μl of 0.2 N NaOH. The enzyme activity was determined by measuring the absorption at 405 nm with suitable corrections for absorption of the test substances and of p-nitrophenyl phosphate. The results were expressed as percent of the control by comparing the amount of p-nitrophenol formed in the test substance-treated samples (nmol / min / mg protein) with the amount in the untreated samples. The mean and the standard deviation were calculated, the IC50 values were determined by regression analysis of the linear part of the inhibition curves.

Table 2: Biological activity

It can be seen from the table that the compounds of the formula I inhibit the activity of phosphotyrosine phosphatase 1 B (PTP1 B) and are therefore very suitable for lowering the blood sugar level. They are particularly suitable for Treatment of type I and II diabetes, insulin resistance, dyslipidemia, metabolic syndrome / syndrome X, pathological obesity and for weight loss in mammals.

Compounds of the formula I are also suitable, because of their inhibition of PTP1 B, for the treatment of hyperglycerimia, high blood pressure, atherosclerosis, malfunctions of the immune system, autoimmune diseases, allergic diseases such as e.g. Asthma, arthritis, osteoarthritis, osteoporosis, proliferation disorders such as cancer and psoriasis, diseases with reduced or increased production of growth factors, hormones or cytokines that trigger the release of growth hormones.

The compounds are also suitable for treating diseases of the nervous system, such as Alzheimer's or multiple sclerosis. The compounds are also useful for treating sensory disorders and other psychiatric indications such as depression, anxiety, anxiety neuroses, schizophrenia, treating disorders associated with circadian rhythm, and treating drug abuse. They are also suitable for the treatment of sleep disorders, sleep apnea, female and male sexual disorders, inflammation, acne, skin pigmentation, steroid metabolism disorders, skin diseases and mycoses.

The preparation of Example 4 is described in detail in Table 1 below, the other compounds of the formula I were obtained analogously:

Experimental part:

A solution of (2-fluoro-5-nitrobenzylbromide (30 g, 0.128 mol) in acetonitrile (250 mL) is added to a solution of Na ₂ S0 ₃ (27.36 g, 0.128 mol) in H 0 (375 mL) and the mixture is stirred at RT for 24 h, the solvent is distilled off in vacuo, the residue is stirred with 100 ml of isopropanol, the solid is filtered off and washed with a little isopropanol or diethyl ether.

Yield: 28.15 g

The sodium salt of sulfonic acid 1 (35.19 g, 0.1368 mol) is placed in POCI ₃ (430 mL) and then PCI ₅ (28.78 g, 0.137 mol) is added. The mixture is heated under reflux for 5 h. For working up, the mixture is concentrated in vacuo and the residue is poured onto ice / water. The reaction product separates out as a light yellow solid, which is filtered off

Yield: 30.3 g

A solution of sulfonic acid chloride 1 (30.3 g, 0.12 mol) in CH ₂ Cl ₂ (125 mL) is added dropwise to concentrated ammonia (90 mL, 1, 2 mol) at RT. The mixture is stirred at RT for 20 h and then acidified to pH 1 with HCl (1 n). The organic phase is then distilled off under reduced pressure, the reaction product separating out as a light yellow solid. The reaction product is then filtered off. Yield 25.01 g (89.4%).

Diazabicycloundecene (34.1 g, 33.42 mL, 0.22 mol) is added at RT to a solution of compound 1 (25 g, 0.107 mol) in DMF (1 L) and the reaction mixture is stirred at 130 ° C. for 2 h , The solvent is then distilled off in vacuo, water (400 ml) is added to the residue, HCl (2n, 400 ml) is added and the product is extracted several times with dichloromethane. The combined organic phases are dried (Na ₂ S0 ₄ ) and the solvent is distilled off under reduced pressure. The remaining residue is stirred with a little cold isopropanol and the reaction product is then filtered off.

Yield: 20.8 g (91.3%).

535 mg of the nitro compound are dissolved in 100 mL methanol / THF mixture (1: 1) and 5 mol% Pd (10% on activated carbon) is added. The mixture is then hydrogenated with hydrogen in a hydrogenation apparatus at room temperature until the hydrogen uptake has ended (reaction time: 1 h). For working up, the catalyst is filtered off through Celite® filter aid and the filtrate is concentrated under reduced pressure. The oily residue is stirred with a little diethyl ether, filtered off, washed with n-pentane and dried in vacuo.

Yield: 397 mg (86% of theory)

1.84 g (10 mmol) of the aniline prepared above are suspended in 240 ml of absolute dichloromethane and with stirring at 20 ° C. with 2.55 g (11 mmol)

1, 1 thiocarbonyldi-2 (1 H) -pyridone added. The reaction mixture is stirred at 20 ° C. for 5 h.

For working up, the reaction mixture is washed 3 times with 50 ml of water and the organic phase is then dried with Na ₂ S0 ₄ and filtered off from the drying agent.

After removing the solvent under reduced pressure, a light yellow oil is obtained, which crystallizes after the addition of a little diethyl ether.

2.12 (9.4 mmol) of yellowish crystals are obtained; Yield 94% of theory MS (ES +): 227.2

1H-NMR (500 MHz, d ₆ -DMSO): δ = 4.57 (s, 2 H), 6.85 (d, J = 8.56 Hz, 1 H), 7.33 (ps d, J = 8.56 Hz, 1 H), 7.40 (ps s, 1 H), 10.84 (br s, 1 H)

226 mg (1 mmol) of the isothiocyanate prepared above are abs in 10 ml. Dissolved tetrahydrofuran and with stirring with 339 mg (1.5 mmol) of 2-azido-1- [3,5-di (tert-butyl) -4-hydroxy-phenyl] -ethan-1-one, prepared from 2-bromo-1 - [3,5-di (tert-butyl) -4-hydroxy-phenyl] -ethan-1-one by reaction with sodium azide in DMF as solvent, and 315 mg (1.2 mmol) of triphenylphosphine. The reaction mixture is heated under reflux of the solvent for 1 h. For working up, the reaction solution is concentrated under reduced pressure and the remaining oily residue is chromatographed as a mobile phase by means of chromatography on silica gel (40-63 μ, Merck) with ethyl acetate / heptane, mixing ratio 1: 1

Yield 288 mg (63% of theory) MS (ES +): 455.99 1 H-NMR (500 MHz, d ₆ -DMSO): δ = 1.42 (s, 18 H), 4.64 (s, 2 H), 6.82 (d, J = 8.6 Hz, 1 H), 7.15 (s, 1 H), 7.22 (s, 1 H), 7.31 (s, 2 H), 7.48 (dd, J = 8.6 and 2.1 Hz, 1 H) , 7.70 (d, J = 2.1 Hz, 1 H), 10.11 (s, 1 H), 10.15 (s, 1 H)

Claims

Patent claims:

Compounds of formula I,

in what mean

X O, C-R2;

Y O, C-R2, where one of the groups X and Y is always O and the other is C-R1;

R1, R2 independently of one another H, aryl, COOH, (dC ₆ ) -alkylene-COOH, - COO (dC ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-COO (C ₁ -C ₆ ) -alkyl, (CC ₆ ) alkyl, (C ₂ -

C ₆ ) -alkenyl, (dC ₆ ) -alkylene-aryl, heterocycle, (dC ₆ ) -alkylene-heterocycle, CF ₃ , OCF ₃ , CN, (CH ₂ ) ι _-6 -OH, 0- (Cι-C ₆₎ -alkyl, CO- (CC ₆₎ - alkyl, -C (0) 0-alkyl, COOH, CON (R9) (R10) may be substituted with the aryl radicals and the heterocyclic radicals mono- or polysubstituted with F, Cl, Br, (CH ₂ ) o- ₂ OH, (CC ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, CF ₃ ,

OCF ₃ , N (R9) (R10), piperidinone, piperazine, piperazinone, N- (CC ₆ -alkylene) -piperazine, N- (-CC ₆ -alkylene) -piperazinone, morpholine, thiomorpholine, N0 ₂ , CN, 0- (dC ₆ ) -alkyl, S (O) ₀ - ₂ - (C ₁ -C ₆ ) -alkyl, S0 ₂ - N (R9) (R10), CO- (dC ₆ ) -alkyl, -COOH, (dC ₆ ) -alkylene-COOH, COO (CC ₆ ) -alkyl, (CrC ₆ ) -alkylene-COO (dC ₆ ) -alkyl, (C ₃ -C ₁₀ ) -cycloalkyl, phenyl, these being piperidinone, piperazine, Piperazinone, N- (dC ₆ -alkylene) - Piperazine, N- (CC ₆ -alkylene) -piperazinone, morpholine, thiomorpholine and phenyl rings can be substituted one or more times with F, Cl, Br, (CH ₂ ) ₀ - ₂ OH, COOH, CN, N0 ₂ , -0- (dC ₆ ) -alkyl, -NH-0- (dC ₆ ) -alkyl, - (CO) -NH-O- (Cι-C ₆ ) -alkylene-N (R9) (R10), - (COHCrC ₆ ) -Alkyl, - (dC ₆ ) -alkyl, CF ₃ , OCF ₃ , N (R9) (R10);

R3 H, (CC ₆ ) -alkyl, (dC ₆ ) -alkylene-aryl, -C (0) -aryl, (CC ₆ ) -alkylene-

Heterocycle, CO- (dC ₆ ) -alkyl, the aryl and heterocyclic radicals one or more times with F, Cl, Br, (CC ₆ ) -alkyl, COOH, COO (C Ce) -alkyl, CF ₃ or OCF ₃ can be substituted;

N (R9) (R10), CN, 0- (CC ₆ ) alkyl, CO- (dC ₆ ) alkyl, COOH, (dC ₆ ) alkylene-COOH, CON (R9) (R10), (dC ₆ ) -Alkylene-CON (R9) (R10), COO (C _r C ₆ ) -alkyl, (dC ₆ ) -alkylene-COO (dC ₆ ) -alkyl, S (O) ₀ - ₂ - (CrC ₆ ) - Alkyl, S (0) ₂ -

N (R9) (R10), CH2OH, CH2OCH3;

R 9 H, (dC ₄ ) alkyl;

R 10 H, (dC ₄ ) alkyl; or

and their physiologically tolerable salts.

2. Compounds of formula I, according to claim 1, characterized in that mean

R1 aryl, (dC ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (dC ₆ ) alkylene aryl, heterocycle,

(dC ₆ ) alkylene heterocycle, CF ₃ , OCF ₃ , CN, (CH ₂ ) _1-6 -OH, 0- (dC ₆ ) alkyl, CO- (CC ₆ ) alkyl, C (0) 0 -alkyl, COOH, CON (R9) (R10), where the aryl radicals and the heterocyclic radicals can be substituted one or more times with F, Cl, Br, (CH ₂ ) _0-2 OH, (CC ₆ ) -alkyl, ( C ₂ -C ₆ ) alkenyl, (C ₂ - C ₆ ) alkynyl, CF ₃ , OCF ₃ , N (R9) (R10), piperidinone, piperazine, piperazinone,

N- (-C-C ₆ -alkylene) -piperazine, N- (-C-C ₆ -alkylene) -piperazinone, morpholine, thiomorpholine, N0 ₂ , CN, 0- (dC ₆ ) -alkyl, S (0) o _{- 2} - (CC ₆ ) -alkyl, S0 ₂ - N (R9) (R10), CO- (CC ₆ ) -alkyl, -COOH, (CC ₆ ) -alkylene-COOH, -COO (CC ₆ ) -alkyl, (C ₀ -C ₆ ) alkylene -COO (CC ₆ ) alkyl, C ₃ -C ₁₀ cycloalkyl, phenyl, these being piperidinone, piperazine, piperazinone, N- (dC ₆ alkylene) -

Piperazine, N- (dC ₆ -alkylene) -piperazinone, morpholine, thiomorpholine and phenyl rings can be substituted one or more times with F, Cl, Br, (CH ₂ ) o- ₂ θH, COOH, CN, N0 ₂ , -0- (CC ₆ ) alkyl, -NH-0- (dC ₆ ) alkyl, - (CO) -NH-0- (dC ₆ ) alkylene-N (R9) (R10), - (CO) - (CC ₆ ) alkyl, - (dC ₆ ) alkyl, CF ₃ , OCF ₃ , N (R9) (R10);

R2 H, aryl, COOH, (C ₁ -C ₆ ) alkylene-COOH, -COO (dC ₆ ) alkyl, (dC ₆ ) -

Alkylene-COO (CC ₆ ) alkyl; (C ₁ -C ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (CC ₆ ) alkylene aryl, heterocycle, (CC ₆ ) alkylene heterocycle, CF ₃ , OCF ₃ , CN, - ( CH ₂ ) ι- 6-OH, 0- (dC ₆ ) alkyl, CO- (CC ₆ ) alkyl, C (0) 0-alkyl, COOH,

CON (R9) (R10), where the aryl radicals and the heterocyclic radicals can be substituted one or more times with F, Cl, Br, (CH ₂ ) o- ₂ OH, (d-Cβ) - alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₆ ) alkynyl, CF ₃ , OCF ₃ , N (R9) (R10), piperidinone, piperazine, piperazinone, N- (CrC ₆ -alkylene) -piperazine, N- (CC ₆ -alkylene) -piperazinone, morpholine, thiomorpholine, N0 ₂ , CN, O- (Cι-Ce) -

Alkyl ,, S (0) o _-2 - (CrC ₆ ) alkyl, SO ₂ -N (R9) (R10) _, CO- (CC ₆ ) alkyl, -COOH, (d-Ce ^ alkylene-COOH ^ COO ^ rCβ ^ alkyl, (C C6) alkylene-COO (Cι-C ₆ ) - Alkyl, C ₃ -Cι ₀ cycloalkyl, phenyl;

Heterocycle, CO- (dC ₆ ) alkyl;

R4, R5 independently of one another H, F, Cl, Br, (-CC ₆ ) alkyl, CF ₃ , OCF ₃ , N0 ₂ ,

N (R9) (R10), CN, 0- (dC ₆ ) alkyl, CO- (dC ₆ ) alkyl, COOH, (dC ₆ ) alkylene-COOH, -CON (R9) (R10), (CC ₆ ) alkylene-CON (R9) (R10), COO (dC ₆ ) alkyl, (dC ₆ ) alkylene-COO (dC ₆ ) alkyl, S (O) _0-2 - (CC ₆ ) alkyl , S (0) ₂ -N (R9) (R10), CH ₂ OH, CH ₂ OCH ₃ ;

R6, R7 independently of one another H, F, Cl, Br, (dC ₆ ) alkyl, cyclopropyl,

R 8 H, CH ₃ , CF ₃ , CH ₂ OH;

R 9 H, (CC ₄ ) alkyl;

R 10 ^' H, (CC ₄ ) alkyl; or

and their physiologically tolerable salts.

3. Compounds of formula I, according to claim 1 or 2, characterized in that mean

R1 phenyl, naphthyl, thionaphthyl, pyridyl, where phenyl, naphthyl,

Thionaphthyl and pyridyl can be substituted one or more times with F, Cl, Br, (CH ₂ ) _0-2 OH, (CC ₆ ) alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, CF ₃ , OCF ₃ , N ( R9) (R10), piperidinone, piperazine, piperazinone, N- (CC ₆ - alkylene) -piperazine, N- (dC ₆ -alkylene) -piperazinone, morpholine, thiomorpholine, N0 ₂ , CN, 0- (CC ₆ ) - Alkyl, S (O) ₀ . ₂ - (-C ₆ -C) alkyl, S0 ₂ - N (R9) (R10), CO- (-C ₆ -C) alkyl, COOH, (dC ₆ ) -alkylene-COOH, COO (d-

C ₆ ) -alkyl, (CC ₆ ) -alkylene-COO (-C-C ₆ ) -alkyl, C ₃ -Cι ₀ -cycloalkyl, phenyl, these piperidinone, piperazine, piperazinone, N- (dC ₆ -alkylene) - Piperazine, N- (dC ₆ -alkylene) -piperazinone, morpholine, thiomorpholine and phenyl rings can be substituted one or more times with F, Cl, Br, (CH ₂ ) _0-2 OH, COOH, CN, N0 ₂ , -0- (dC ₆ ) alkyl, -NH-0- (CC ₆ ) alkyl, -

(CO) -NH-0- (-Cι-C ₆ ) alkylene-N (R9) (R10), - (CO) - (CC ₆ ) alkyl, - (CC ₆ ) - alkyl, CF ₃ , OCF ₃ , N (R9) (R10);

R2 H, (CC ₆ ) alkyl, COOH, (CC ₆ ) alkylene-COOH, -COO (CC ₆ ) alkyl, (d-C ₆ ) alkylene-COO (dC ₆ ) alkyl;

Heterocycle, CO- (CC ₆ ) alkyl;

R4, R5 H;

R6, R7 H;

R 8 H;

R 9 H, (dC ₄ ) alkyl;

R 10 H, (dC ₄ ) alkyl;

and their physiologically tolerable salts.

4. Compounds of formula I, according to one or more of claims 1 to 3, characterized in that mean

R1 phenyl, where phenyl, naphthyl, thionaphthyl and pyridyl can be substituted one or more times with F, Cl, Br, (CH ₂ ) o- ₂ OH, (d-Cey-alkyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₆ ) alkynyl, CF ₃ , OCF ₃ , N (R9) (R10), piperidinone, piperazine, piperazinone, N- (dC ₆ alkylene) piperazine, N- (dC ₆ alkylene) - Piperazinone, morpholine, thiomorpholine, N0 ₂ , CN, 0- (dC ₆ ) alkyl, S (O) _0- ₂ - (dC ₆ ) alkyl, S0 ₂ -N (R9) (R10) _, CO- (CC ₆ ) alkyl, COOH, (CC ₆ ) -

Alkylene-COOH, COO (dC ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylene-COO (C ₁ -C ₆ ) -alkyl, C ₃ - cio-cycloalkyl, phenyl, these being piperidinone, piperazine, piperazinone, N- (-C ₆ alkylene) piperazine, N- (dC ₆ alkylene) piperazinone, morpholine, thiomorpholine and phenyl rings can be substituted one or more times with F, Cl, Br, (CH ₂ ) o- ₂ - OH, COOH, CN, N0 ₂ , -0- (dC ₆ ) alkyl,

NH-0- (dC ₆ ) -alkyl, - (CO) -NH-0- (CC ₆ ) -alkylene-N (R9) (R10), - (CO) - (d- C ₆ ) -alkyl, - (dC ₆ ) alkyl, CF ₃₎ OCF ₃ , N (R9) (R10);

R2 H, (dC ₆ ) alkyl, -C (0) 0- (dC ₆ ) alkyl, - (C ₁ -C ₆ ) alkylene-C (0) 0- (CrC ₆ ) alkyl, -COOH , - (CC ₆ ) alkylene-COOH;

R3 H, (dC ₆ ) alkyl, (dC ₆ ) alkylene aryl, -C (0) aryl, (dC ₆ ) alkylene-

Heterocycle, CO- (C ₁ -C ₆ ) alkyl;

R4, R5 H;

R6, R7 H;

R 8 H;

R 9 H; R 10 H

and their physiologically tolerable salts.

5. Use of the compounds according to one or more of claims 1 to 4 for the manufacture of a medicament.

6. Medicament containing one or more of the compounds according to one or more of claims 1 to 4.

7. Medicament containing one or more of the compounds according to one or more of claims 1 to 4 and at least one further active ingredient.

8. Medicament according to claim 7, characterized in that it is one or more as a further active ingredient

Antidiabetics, hypoglycemic active ingredients, HMGCoA reductase inhibitors, Cholesterinresorptionsinhibitoren, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha / gamma agonists, fibrates, MTP inhibitors, bile acid, CETP inhibitors, polymeric bile acid adsorbers, LDL receptor inducers, ACAT inhibitors, antioxidants , lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthetase ^antagonists' inhibitors, lipoprotein (a), lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, σ-glucosidase inhibitors, dependent on the ATP-potassium channel of the Beta-active agents, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists,? 3 agonists, MSH (melanocyt stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed sertonin and noradrenergic compounds, 5HT agonists , Bombesin agonists, galanin antagonists, growth hormones, growth hormone releasing compounds, TRH agonists, decoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, doprexin), Contains lipase / amylase inhibitors, PPAR modulators, RXR modulators or TR - /? - agonists or amphetamines.

9. Use of the compounds according to one or more of claims 1 to 4 for the manufacture of a medicament for lowering blood sugar.

10. Use of the compounds according to one or more of claims 1 to 4 for the manufacture of a medicament for the treatment of type II diabetes.

11. Use of the compounds according to one or more of claims 1 to 4 for the manufacture of a medicament for the treatment of lipid and carbohydrate metabolism disorders.

12. Use of the compounds according to one or more of claims 1 to 4 for the manufacture of a medicament for the treatment of arteriosclerotic

Phenomena.

13. Use of the compounds according to one or more of claims 1 to 4 for the manufacture of a medicament for the treatment of insulin resistance.

14. A process for the preparation of a medicament containing one or more of the compounds according to one or more of claims 1 to 4, characterized in that the active ingredient is mixed with a pharmaceutically suitable carrier and this mixture is brought into a form suitable for administration.